ABSTRACT
Approximately 75% of breast cancers express estrogen receptor α (ERα) and depend on estrogen signals for continued growth. Aromatase inhibitors (AIs) prevent estrogen production and inhibit ER signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the upregulation of alternative growth signals. The mechanisms that drive this resistance-especially epigenetic events that alter gene expression-are, however, not well understood. Genome-wide DNA methylation and expression analysis of cell line models of acquired AI resistance indicated that prostaglandin E2 receptor 4 (PTGER4) is upregulated after demethylation in resistant cells. Knockdown and inhibitor studies demonstrate that PTGER4 is essential for estrogen-independent growth. Our exploratory analysis of downstream signaling indicates that PTGER4 likely promotes AI resistance via ligand-independent activation of the ERα-cofactor CARM1. We believe that we have discovered a novel epigenetic mechanism for altering cell signaling and acquiring endocrine therapy resistance. Our findings indicate that PTGER4 is a potential drug target in AI-resistant cancers. In addition, the epigenetic component of PTGER4 regulation suggests that further study of PTGER4 may yield valuable insights into how DNA methylation-targeted diagnoses and treatments can improve AI-resistant breast cancer treatment.
Subject(s)
Breast Neoplasms/genetics , Drug Resistance, Neoplasm/genetics , Epigenesis, Genetic , Receptors, Prostaglandin E, EP4 Subtype/genetics , Antineoplastic Agents/therapeutic use , Aromatase Inhibitors/therapeutic use , Breast Neoplasms/drug therapy , Cell Proliferation , DNA Methylation , DNA, Neoplasm/metabolism , Estrogen Receptor alpha/metabolism , Female , Gene Expression Regulation, Neoplastic , Humans , MCF-7 Cells , Protein-Arginine N-Methyltransferases/metabolism , Receptors, Prostaglandin E, EP4 Subtype/metabolism , Signal TransductionABSTRACT
This study was conducted to analyze the clinical significance of follow-up diagnostic methods of atypical squamous cells (ASC) (the 2001 Bethesda System) cases according to age. A computerized search of the cytology database was performed to retrieve all cases diagnosed as ASC from 2001 to 2003. The pathologic reports for all follow-up diagnoses were reviewed. We divided the patients into two groups according to their age, younger than 50 years of age and 50 years and older, and follow-up diagnoses were compared between the two groups. ASC was identified in 1035 (2.0%) of 49,882 women screened, and a total of 914 patients were eligible. In atypical squamous cells of undetermined significance (ASC-US) cases, colposcopically directed biopsy showed CIN I (CIN is cervical intraepithelial neoplasia) or higher grade lesions in 34.9% of cases younger than 50 years of age and in 17.4% of cases 50 years and older (P= 0.000). However, repeat Pap smears and human papillomavirus DNA testing showed no differences between the two groups. In contrast, the three methods did not exhibit significant difference between the two groups in patients with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) (P= 0.743). Colposcopically directed biopsy for the ASC-US was more useful in patients younger than 50 years of age than in those who were 50 years and older. It is suggested that age should be considered in deciding follow-up diagnostic methods in patients with ASC-US.
